The role of zinc in various agricultural, animal husbandry and animal and human nutritional and therapy requirements has been well established. The need for intervention rather than relying upon chance for adequate zinc provision is apparent as demonstrated by the United States Department of Agriculture survey revealing that the earth in 32 of the states of the United States is zinc deficient. Accordingly, it is common to treat soils or crops with zinc for an optimum harvest.
Domestic animals, zinc enrichment of feed is standard practice in the commercial husbandry of beef and dairy cattle, horses, mice, pheasants, quail poultry, e.g. chickens and turkeys, and fish, catfish and trout. Since zinc deficiency is no general terrestrially, deficiency may also be prevalent in man and other animals particularly in times of increased zinc need.
Zinc is known to be required by at least 18 enzymes and enzyme cofactors including alkaline phosphatase, carbonic anhydrase, carboxypeptidase, dehydrogenases for ethanol, glutamic acid and lactic acid, arginase, carnosinase, dehydropeptidase, glycylglycine, dipeptidase, histidine deaminase, tripeptidase, oxaloacetic carboxylase, lecithinase and enolase.
Zinc deficiency retards growth in cattle, sheep, turkeys, pheasant, chickens, rats, mice and humans. In pigs, calves and poultry, parakeratoses, reddened sore skin and dermatitis are caused by inadequate zinc in the diet. Adequate zinc plasma and tissue levels are necessary to avoid teratogenicity in pregnant animals and to permit egg shell and bone development as well as general growth development and sexual maturation.
While zinc supplement to the diet as by administration of zinc oxide, zinc carbonate, zinc chloride, zinc sulfate, zinc gluconate, zinc lactate, or zinc metal in finely divided form may be advantageous, in man particularly it has been found that the absorption of zinc from the gastrointestinal tract is often inhibited by food material present therein. Diets containing protein or phytic acid from bean, particularly soybean, or cereal, free amino acids or ethylenediamine tetraacetic acid, inactivate or make unavailable the dietary zinc. In various disease conditions, the zinc serum and tissue levels are known to be implicated and enhancing the zinc levels is useful therapy.
Enhanced zinc level has been indicated in the treatment of animals, particularly humans, in burns, serious intestinal fistulas, infarctions, malabsorption, wounds, surgery, dental extraction wounds, idiopathic hypogeusia, venous leg ulcers, decubitus ulcers, syndrome of dwarfism and hypogonadism, while lowered zinc serum and tissue levels are associated with regional enteritis, sickle cell anemia and disease, rheumatoid arthritis, acrodermatitis enteropathica, peptic ulcers, porphyria, hepatic cirrhosis, bone healing, psoriasis, postintubation tracheal granuloma, acute myocardial infarction, renal disease, anemia and geophagia, diabetes mellitus, thalassemia, oral contraception with estrogens, cystic fibrosis, Down's syndrome, pernicious anemia, or corticosteroid antiinflammatory use. In these latter situations where zinc plasma levels have been found to be often lower than normal, raising the zinc plasma and tissue level is thus indicated and has been effective in ameliorating or eliminating some of the disease condition or accelerating healing.
The presently recommended daily adult dietary requirement of zinc is 15 mg. Negative zinc balance ordinarily occurs at an intake of 5 to 6 mg of zinc per day and this is accompanied by the daily loss of about 6 mg of zinc per day by excretion via feces, urine and perspiration. In hot climates the loss in perspiration may amount to 5 mg of zinc per day. While attempts have been made with varying degrees of success to alleviate zinc deficiency in animals and humans by adding a zinc source to the diet, the therapeutic result desired has not been readily achievable because of either the reaction between ionic zinc and gastrointestinal contents or the gastric discomfort occasioned by oral administration of zinc compounds. An attempt to overcome this problem is described in U.S. Pat. No. 3,941,818 issued Mar. 2, 1976 concerned with zinc methionine complexes as a zinc dietary source but does not achieve the dramatic zinc plasma and tissue levels and efficiency obtained by the instant invention even without optional supplementary dietary zinc. In accordance with the present invention, the administration of .alpha.-mercapto-.beta.-aryl acrylic acid or its salt facilitates absorption of dietary zinc, dramatically raises the zinc serum and tissue levels and reduces the rate of elimination of zinc from the body.
While .alpha.-mercapto-.beta.-aryl acrylic acids are well known, their utilization in therapeutics is exceedingly rare. These compounds are most commonly prepared by the procedure of Campaigne, E. and Cline, R., J. Org. Chem. 21, 32 (1956) from rhodanine and the corresponding aryl aldehyde. U.S. Pat. No. 3,452,039 describes a number of .alpha.-mercapto-.beta.-phenylacrylic acids and their substitution products utilized as intermediates in the manufacture of benzothiophene hypocholesterolemic agents. Various .alpha.-mercapto-.beta.-substituted arylacrylic acids were prepared and tested by Ravazzoni, C. et al. Ann. Chim. (Rome) 52, 305-12 (1962) Chem. Abst. 57, 9833 g and reported to be effective plant growth substances. Haskel, et al. J. Med. Chem. 13, 697 (1970) prepared and tested .alpha.-mercapto-.beta.-aryl acrylic acids including substituted phenyl, substituted thienyl and substituted pyridyl analogs for neuraminidase inhibition and administered the most potent enzyme inhibitors, e.g. .alpha.-mercapto-.beta.-4-nitrophenyl acrylic acid orally and intraperitoneally to mice without increase in survival against influenza virus. Being interested in antibacterial and antifungal activity Foy et al., J. Pharm. Sci. 61, 1209 (1972) tested therefor .alpha.-mercaptocinnamic acid as having some activity in this regard and incidentally relatively weak metal binding avidity for copper, aluminum and iron. Activity in vitro in inhibiting rat heart mitochondria pyruvate transport sensitivity was reported for .alpha.-thiofuranopyruvate, otherwise named .alpha.-mercapto-.beta.-2-furyl, acrylic acid, by Halestrap, A., Biochem. J. 148 (1) 85 (1975) at page 90. No reference more pertinent than these are known to the applicants.